EP2991632A1 - Formualtions de tigécycline - Google Patents

Formualtions de tigécycline

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Publication number
EP2991632A1
EP2991632A1 EP14792101.9A EP14792101A EP2991632A1 EP 2991632 A1 EP2991632 A1 EP 2991632A1 EP 14792101 A EP14792101 A EP 14792101A EP 2991632 A1 EP2991632 A1 EP 2991632A1
Authority
EP
European Patent Office
Prior art keywords
tigecycline
arginine
composition
solid
stored
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP14792101.9A
Other languages
German (de)
English (en)
Other versions
EP2991632A4 (fr
Inventor
Beena Uchil
Shweta Mowli
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fresenius Kabi USA LLC
Original Assignee
Fresenius Kabi USA LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fresenius Kabi USA LLC filed Critical Fresenius Kabi USA LLC
Publication of EP2991632A1 publication Critical patent/EP2991632A1/fr
Publication of EP2991632A4 publication Critical patent/EP2991632A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/65—Tetracyclines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • Glycylcyclines are a class of antibiotics that were developed to address the increase in bacterial resistance to the tetracycline class of antibiotics. Glycylcyclines are synthetic derivatives of the tetracyclines, and can be active against the resistant strains of bacteria originally targeted by the tetracyclines, as well as bacteria that have developed resistance to non- tetracycline antibiotics. The first of the glycylcyclines to be approved in the U.S. for use as an antibiotic was tigecycline.
  • tigecycline is (4S,4aS,5aR,12aS)-9-[2-( ⁇ er ⁇ -bu ⁇ ylamino)ace ⁇ amido]-4,7-bis(dime ⁇ hyl-amino)- 1 ,4,4 ⁇ ,5,5 ⁇ , ⁇ ,1 1 ,12a-oc ⁇ ahydro-3,l 0,12,12a- ⁇ e ⁇ rahydroxy-l ,1 1 -dioxo-2- naphthacenecarboxamide, and a representative chemical structure is shown in FIG. 1 .
  • Tigecycline has been approved in the U.S. for treatment of a variety of bacterial infections, including complicated skin and skin structure infections, complicated intra-abdominal infections, and community-acquired bacterial lung infections.
  • An approved treatment regimen for adults includes administration of an initial does of 100 milligrams (mg) tigecycline, followed by administration of a maintenance dose of 50 mg tigecycline every 12 hours, where each administration is performed through intravenous infusion over 30-00 minutes.
  • tigecycline As tigecycline has poor oral bioavailability, it typically has been provided to medical personnel as a lyophilized solid, which is then
  • tigecycline that is commercially available at present is sold under the TYGACIL trademark.
  • TYGACILTM for Injection Pfizer Inc.; New York, New York, USA
  • TYGACILTM for Injection is currently available as a lyophilized powder containing 53 mg of tigecycline and 10 ⁇ mg lactose monohydrate, and including hydrochloric acid and/or sodium hydroxide as pH modifiers.
  • TYGACILTM is reconstituted for administration by combining the lyophilized powder with 5.3 milliliters (mL) of a reconstitution liquid (such as 0.9% sodium chloride), to provide a solution having a tigecycline concentration of 10 milligrams per milliliter (mg/mL). An aliquot of 5 mL of this solution, which contains 50 mg tigecycline, is diluted prior to administration with 100 mL of an infusion liquid to provide a final concentration of 0.5 mg/mL.
  • a reconstitution liquid such as 0.9% sodium chloride
  • two vials of TYGACILTM may be reconstituted in 5.3 mL of a reconstitution liquid each, and then both reconstituted liquids may be added to 100 mL of an infusion liquid, to provide a final
  • Tigecycline degrades under ambient conditions, and this degradation can occur by two pathways.
  • tigecycline can oxidize, such as by forming a double bond between the position 6 and position 5a ring atoms.
  • This oxidation product may be referred to as the "6- ene" impurity, and is presently believed to be represented by the chemical structure shown in FIG. 2, where the arrow points to the double bond between positions 6 and 5a of the ring system.
  • tigecycline can undergo epimerization to reverse the stereochemistry of the position 4 ring atom, which is bonded to one of the dimethylamino
  • the resulting epimer is presently believed to be represented by the chemical structure shown in in FIG. 3, where the arrow points to the position 4 ring atom. Both of these degradation pathways convert the pharmacologically active tigecycline molecule into a species that is inactive or that has an antimicrobial activity that is substantially lower than that of tigecycline.
  • a change to the processing or formulation of tigecycline that minimizes one of the degradation pathways typically enhances the other degradation pathway.
  • lyophilized tigecycline formulation various modifications to the chemical composition of the formulation have been reported to improve the stability of tigecycline.
  • Combining tigecycline with a carbohydrate and either an acid or a buffer resulted in lyophilized formulations in which tigecycline was less susceptible to both oxidative degradation and epimerization than when tigecycline was lyophilized with no excipients.
  • the TYGACILTM TYGACILTM
  • formulation which includes tigecycline, lactose monohydrate and a pH modifier, has improved stability relative to lyophilized formulations of tigecycline alone. See U.S. Patent No. 7,879,828.
  • tigecycline was combined with ascorbic acid (vitamin C), an ascorbate salt, threonine or serine instead of with a carbohydrate. Lyophilized formulations containing ascorbic acid or threonine stabilized tigecycline at levels comparable to that of TYGACILTM. See Chinese patent publication CN 102138925 A.
  • tigecycline have improved the stability of tigecycline
  • lyophilized powders containing tigecycline must still be stored in a controlled environment in order to inhibit degradation of the tigecycline.
  • Current protocols for TYGACILTM require the lyophilized powder to be stored at temperatures from 20 °C to 25 °C.
  • reconstituted liquids containing tigecycline also must be maintained in a controlled environment.
  • Current protocols for TYGACILTM allow for reconstituted and diluted liquids to be maintained at room temperature for 24 hours, or to be refrigerated at temperatures from 2 °C to 8 °C for 48 hours.
  • hospital staff presently is burdened with the need to prepare tigecycline mixtures close to the time of administration, and to monitor the temperature and/or administration time of the reconstituted mixtures, all in the context of caring for a critically infected patient.
  • a lyophilized formulation of tigecycline to be stable at a temperature of 25 °C for more than 2 years and/or to be stable at temperatures above 25 °C for at least 2 years.
  • a reconstituted formulation of tigecycline to be stable at temperatures of 25 °C for more than 24 hours and/or to be stable at temperatures above 25 °C for at least 24 hours.
  • stabilized formulations would be convenient to prepare, store, reconstitute and administer.
  • a composition that includes tigecycline and arginine, where the composition is a solid.
  • a composition is provided that includes from 50 to 60 mg tigecycline, and arginine, where the composition is a solid.
  • the mass ratio of arginine to tigecycline is from 1 :0.5 to 1 :5.
  • the composition is combined with 5.3 ml_ of an aqueous carrier liquid to form a solution, the solution has a pH of from 4 to 8.
  • a method of stabilizing a tigecycline composition comprises forming a liquid mixture including a solvent,
  • FIG. 1 depicts a chemical structure of tigecycline.
  • FIG. 2 depicts a chemical structure of the "6-ene” degradation product of the oxidation of tigecycline.
  • FIG. 3 depicts a chemical structure of the "epimer” degradation product of the epimerization of tigecycline.
  • the invention provides a solid composition comprising tigecycline and arginine.
  • solid means a substance that is not a liquid or a gas.
  • a solid substance may have one of a variety of forms, including a monolithic solid, a powder, a gel or a paste.
  • tigecycline is intended to include tigecycline in free base form, as well as salts, hydrates, and solvates of tigecycline.
  • a tigecycline salt is a pharmaceutically acceptable tigecycline salt, such as tigecycline hydrochloride.
  • the tigecycline can be crystalline or amorphous. If crystalline, the tigecycline can be any tigecycline salt.
  • arginine is intended to include L- arginine, D-arginine, or a mixture of L- and D-arginine, and includes arginine in free base form as well as arginine salts.
  • an arginine salt is a pharmaceutically acceptable arginine salt.
  • Exemplary arginine salts suitable for use in the invention include, but are not limited to, hydrochloride, glutamate, butyrate, glycolate, and carbonate salts.
  • the arginine is in free base form.
  • the arginine is L- arginine in free base form.
  • a solid composition that includes tigecycline and arginine may include an amount of tigecycline that is sufficient for a single initial dose of tigecycline, or an amount sufficient for a maintenance dose of tigecycline.
  • a solid composition that includes tigecycline and arginine may include an amount of tigecycline that is sufficient for two or more initial doses of tigecycline, or an amount sufficient for two or more maintenance doses of tigecycline.
  • the amount of tigecycline in the composition may be a different therapeutic amount. For example, the amount of tigecycline in the
  • composition may be an amount sufficient for half of an initial dose, or for half of a maintenance dose.
  • a solid composition that includes tigecycline and arginine may include from 10 to 200 milligrams (mg) tigecycline.
  • the composition includes from 25 to 150 mg tigecycline, from 50 to 150 mg tigecycline, or from 50 to 1 10 mg tigecycline.
  • Presently preferred amounts of tigecycline in the composition include about 53 mg or about 10 ⁇ mg.
  • the amounts of tigecycline recited herein correspond to the free base forms of tigecycline.
  • a solid composition that includes tigecycline and arginine may include an amount of arginine sufficient to stabilize the tigecycline.
  • the amount of arginine in the composition is at most an amount that will dissolve in a sample of aqueous liquid, such as a volume of aqueous liquid used for reconstitution of the solid composition.
  • a solid composition that includes tigecycline and arginine may include from 5 to 1 ,000 mg arginine.
  • the composition includes from 10 to 750 mg arginine, from 25 to 500 mg arginine, from 50 to 200 mg arginine, or from 50 to 300 mg arginine.
  • the composition comprises about 87.5 mg or about 175 mg arginine.
  • the amounts of arginine recited herein correspond to the free base form of arginine.
  • a solid composition that includes tigecycline and arginine may have a mass ratio of tigecycline to arginine of from 1 :0.5 to 1 :5.
  • the term "mass ratio" of two substances means the mass of one substance (SI ) relative to the mass of the other substance (S2), where both masses have identical units, expressed as SI :S2.
  • the solid composition has a mass ratio of tigecycline to arginine from 1 :0.75 to 1 :3, or from 1 :1 to 1 :2.
  • the solid composition has a mass ratio of tigecycline to arginine of 1 :1 , 1 :1 .25, 1 :1.5, 1 :1 .65, 1 :1 .75, or 1 :2.
  • the amount of arginine in the solid composition preferably is from 50 to 100 mg, from 25 to 150 mg, or from 10 to 200 mg.
  • a solid composition that includes tigecycline and arginine may further include an acid and/or a base.
  • the pH of a saturated solution of tigecycline in water is about 8.
  • the amount of the acid and/or base may be an amount sufficient to provide a pH in the range of from 4 to 6 when a composition containing 53 mg tigecycline is reconstituted in 5.3 ml_ of an aqueous carrier liquid, such as 0.9% sodium chloride injection.
  • the amount of the acid and/or base may be an amount sufficient to provide a pH in the range of from 4.25 to 5.75, from 4.5 to 5.75, from 4.5 to 5.5, or from 4.75 to 5.25 when a composition containing 53 mg tigecycline is reconstituted in 5.3 ml_ of an aqueous carrier liquid.
  • hydrochloric acid and/or sodium hydroxide is used to adjust pH.
  • a solid composition that includes tigecycline and arginine may further include one or more other substances.
  • other substances include bulking agents, carriers, diluents, fillers, salts, buffers, stabilizers, solubilizers, preservatives, antioxidants, and tonicity contributors.
  • Substances that may be useful in formulating pharmaceutically acceptable compositions, and methods of forming such compositions, are described for example in Remington: The Science and Practice of Pharmacy, 20 ⁇ h Ed., ed. A. Gennaro, Lippincott Williams & Wilkins, 2000, and in Kibbe, "Handbook of Pharmaceutical Excipients," 3 rd Edition, 2000.
  • a solid composition comprising tigecycline and arginine may be prepared by any suitable method.
  • a solid composition comprising tigecycline and arginine is prepared by forming a liquid mixture that includes a solvent, tigecycline, arginine and optionally one or more other substances, and lyophilizing the liquid mixture.
  • the lyophilizing may include freeze-drying the liquid mixture to provide a solid composition.
  • the liquid mixture may include tigecycline and arginine in the amounts described above.
  • the liquid mixture may further include an acid, a base and/or one or more other substances, as described above.
  • the liquid mixture may include from 0.1 to 10 mL solvent, from 10 to 200 mg tigecycline, and from 5 to 1 ,000 mg arginine.
  • the liquid mixture may include from 0.5 to 7 mL solvent, from 25 to 150 mg tigecycline, and from 10 to 750 mg arginine.
  • the liquid mixture may include from 0.75 to 5 mL solvent, from 50 to 1 10 mg tigecycline, and from 25 to 500 mg arginine.
  • the mass ratio of tigecycline to arginine in the liquid mixture may be from 1 :0.5 to 1 :5, from 1 :0.75 to 1 :3, or from 1 :1 to 1 :2.
  • the solvent, tigecycline, arginine, optional acid, optional base and one or more other optional substances may be combined in any order when forming the liquid mixture.
  • a liquid mixture may be formed by adding the tigecycline and the arginine to a container including the solvent, and then adding the acid and/or base to achieve the desired pH in the liquid mixture.
  • a liquid mixture may be formed by combining the arginine and the solvent in a container, adding the acid and/or base to achieve a first desired pH, adding the tigecycline to the container, and adding the acid and/or base to achieve a final desired pH in the liquid mixture.
  • the liquid mixture preferably has a pH of from 4 to 6. In certain preferred embodiments, the pH of the liquid mixture is 5.1 .
  • the liquid mixture including the solvent, tigecycline, arginine, and any other optional ingredients may be lyophilized to form a solid composition, such as by subjecting the liquid mixture to freeze-drying. Freeze-drying of the liquid mixture may include maintaining the liquid mixture in an inert atmosphere, such as nitrogen or argon. Preferably the liquid mixture is placed in glass vials prior to lyophilization, and the amount of the liquid mixture in each vial is based on the amount of tigecycline intended to be present in the final solid composition in the vial.
  • the temperature of the liquid mixture is lowered to a temperature at or below the solidification point of the liquid mixture. If the liquid mixture forms a glass when cooled, the
  • the solidification point is the glass transition temperature. If the liquid mixture forms crystals when cooled, the solidification point is the eutectic point.
  • the solidified mixture is then dried under vacuum. Typically, the drying process includes a primary drying step in which the temperature of the solidified mixture is raised gradually while most of the water is removed from the mixture by the vacuum, and a secondary drying step in which the
  • Lyophilization may be complete within 48 hours, or may require additional time.
  • the solid composition resulting from the lyophilization typically is sealed for later use. Details regarding the lyophilization process may be found, for example, in
  • the lyophilized solid composition may be stored for later reconstitution and administration.
  • the solid composition is stored at a temperature of from 10 °C to 40 °C, from 15 °C to 35 °C, from 20 °C to 30 °C, or about 25 °C.
  • the solid composition is sealed in the glass vial to protect the composition from moisture in the surrounding environment.
  • a solid composition including tigecycline and arginine may be administered to a patient by combining the composition with an aqueous carrier liquid ⁇ o form an aqueous mixture, and administering the aqueous mixture into the patient by, for example, injection.
  • the aqueous carrier liquid is a pharmaceutically acceptable carrier liquid.
  • pharmaceutically acceptable carrier liquids include water, 0.9% sodium chloride injection, phosphate buffered saline (PBS), 5% dextrose injection, Ringer's solution, and lactated Ringer's solution.
  • the aqueous carrier liquid also may include fixed oils, fatty esters or polyols, particularly if the aqueous mixture for injection is a suspension.
  • the aqueous carrier liquid also may include one or more other substances such as buffers, stabilizers, solubilizers, preservatives and antioxidants.
  • the solid composition dissolves in the aqueous carrier liquid to form a solution.
  • the aqueous carrier liquid is sodium chloride injection (e.g., solutions containing 0.9%, 0.45%, or 0.225% sodium chloride), sterile water for injection, bacteriostatic water for injection (e.g., which may include, for example, either 0.9% benzyl alcohol or a combination of methylparaben and propylparaben), Ringer's solution, lactated Ringer's solution, or 5% dextrose solution.
  • sodium chloride injection e.g., solutions containing 0.9%, 0.45%, or 0.225% sodium chloride
  • sterile water for injection e.g., sterile water for injection
  • bacteriostatic water for injection e.g., which may include, for example, either 0.9% benzyl alcohol or a combination of methylparaben and propylparaben
  • Ringer's solution e.g., lactated Ringer's solution
  • 5% dextrose solution e.g., 5% dextrose solution.
  • the amount of aqueous carrier liquid may be sufficient to provide an initial aqueous mixture containing tigecycline at a concentration of 10 mg/mL. At this concentration, it is convenient to provide a 50 mg or 100 mg dose of tigecycline to a patient, such as by dispensing 5 ml_ or 10 ml_ of the mixture into another aqueous liquid, to form a final mixture for
  • aqueous carrier liquid may be sufficient to provide a final aqueous mixture containing tigecycline at a concentration of at most 1 mg/mL.
  • concentrations of tigecycline in a final aqueous mixture for administration to a patient are from 0.05 to 1 .5 mg/mL, from 0.1 to 1 mg/mL, and from 0.3 to 0.7 mg/mL.
  • concentration of tigecycline present in a final aqueous mixture for administration to a patient is about 0.5 mg/mL, e.g., 0.470 mg/mL.
  • An aqueous mixture formed from the solid composition may be administered to provide an initial dose of 100 mg of tigecycline to a patient.
  • An aqueous mixture formed from the solid composition may be administered to provide a maintenance dose of 50 mg of tigecycline to a patient twice a day. Doses outside of these ranges also may be administered.
  • an initial dose includes 100 mg tigecycline, and subsequent maintenance doses include 50 mg/mL tigecycline. Higher maintenance doses than 50 mg/mL tigecycline may be advisable under certain conditions, such as an insufficient response by the bacterial infection. Maintenance doses below 50 mg/mL of tigecycline may be advisable under certain conditions, such as for pediatric patients or patients having moderate hepatic impairment.
  • the invention also provides a method of treating a bacterial infection in a subject.
  • the method comprises combining a solid composition comprising an effective amount of tigecycline and arginine with an aqueous carrier liquid to form a solution, and administering the solution to the subject.
  • the bacterial infection is a complicated skin or skin structure infection, a complicated intra-abdominal infection, or community- acquired bacterial pneumonia.
  • tigecycline in a solid composition including arginine may be more stable, i.e., less susceptible to degradation, than tigecycline in a solid composition including lactose monohydrate, such as the TYGACILTM formulation (Pfizer Inc.) .
  • degradation of tigecycline includes any conversion of tigecycline into a different substance, including but not limited to the 6-ene oxidation product and/or the epimerization product.
  • Degradation of tigecycline also includes any amount of tigecycline impurities that may be derived from a tigecycline synthesis process, such as chemical intermediates of tigecycline, which may be present in a solid composition.
  • Any suitable analytical method can be used to determine of the amount of tigecycline degradation products in a composition.
  • the method used to determine the amount of tigecycline degradation products in a composition is high-performance liquid chromatography (HPLC) .
  • a solid composition including tigecycline and arginine when stored at 25 °C over a period of 12 months, at most 2.4% of the tigecycline degrades.
  • the term "at most x% of the tigecycline degrades" means that following storage for a given length of time, the composition contains x% or less of tigecycline degradation
  • the amount of tigecycline degradation products present in a composition is calculated based upon the areas under the peaks of tigecycline and the tigecycline degradation products in an HPLC chromatogram.
  • a solid composition including tigecycline and arginine when stored at 25 °C over a period of 12 months, at most 2%, at most 1 .75%, at most 1 .5%, at most 1 .25%, at most 1 %, at most 0.75%, at most 0.5%, or at most 0.3% of the tigecycline degrades.
  • the amount of tigecycline degradation when a solid composition including tigecycline and arginine is stored at 25 °C over a period of 12 months the amount of tigecycline degradation is, for example, 0.3% - 2.4%, 0.3% - 2%, 0.5% - 1 .5%, 0.5% - 1 %, or 0.75% - 1 .25%.
  • a solid composition including tigecycline and arginine when stored at 25 °C over a period of 12 months, af most 0.5% of the tigecycline is converted to the 6-ene degradant, and at most 1 .2% of the tigecycline is converted to the epimer degradant. More preferably, when a solid composition including tigecycline and arginine is stored at 25 °C over a period of 12 months, at most 0.4% of the tigecycline is converted to the 6-ene degradant, and at most 1.0% of the tigecycline is converted to the epimer degradant.
  • a solid composition including tigecycline and arginine when a solid composition including tigecycline and arginine is stored at 25 °C over a period of 12 months, at most 0.3% of the tigecycline is converted to the 6-ene degradant, and at most 0.8% of the tigecycline is converted to the epimer degradant. More preferably, when a solid composition including tigecycline and arginine is stored at 25 °C over a period of 12 months, at most 0.2% of the tigecycline is converted to the 6-ene degradant, and at most 0.6% of the tigecycline is converted to the epimer degradant.
  • a solid composition including tigecycline and arginine when a solid composition including tigecycline and arginine is stored at 25 °C over a period of 12 months, at most 0.1 % of the tigecycline is converted to the 6-ene degradant, and at most 0.5% of the tigecycline is converted to the epimer degradant. More preferably, when a solid composition including tigecycline and arginine is stored at 25 °C over a period of 12 months, at most 0.08% of the tigecycline is converted to the 6- ene degradant, and at most 0.4% of the tigecycline is converted to the epimer degradant.
  • solid compositions of the invention that include tigecycline and arginine may tigecycline from degradation for more than 2 years at room temperature (-25 °C), and for at least 2 years at elevated temperatures above 25 °C.
  • a solid composition including tigecycline and arginine is stored at 40 °C over a period of 6 months, at most 3% of the tigecycline degrades.
  • a solid composition including tigecycline and arginine when stored at 40 °C over a period of 6 months, at most 2.5%, at most 2%, at most 1 .5%, at most 1 %, at most 0.9%, at most 0.8%, at most 0.7%, at most 0.6%, or at most 0.5% of the tigecycline degrades.
  • a solid composition including tigecycline and arginine when stored at 40 °C over a period of 6 months, at most 0.5% of the tigecycline is converted to the 6-ene degradant, and at most 2% of the tigecycline is converted to the epimer degradant. More preferably, when a solid composition including tigecycline and arginine is stored at 40 °C over a period of 6 months, at most 0.4% of the tigecycline is converted to the 6-ene degradant, and at most 1.5% of the tigecycline is converted to the epimer degradant.
  • a solid composition including tigecycline and arginine when a solid composition including tigecycline and arginine is stored at 40 °C over a period of 6 months, at most 0.3% of the tigecycline is converted to the 6-ene degradant, and at most 1.25% of the tigecycline is converted to the epimer degradant. More preferably, when a solid composition including tigecycline and arginine is stored at 40 °C over a period of 6 months, at most 0.2% of the tigecycline is converted to the 6-ene degradant, and at most 1 % of the tigecycline is converted to the epimer degradant.
  • a solid composition including tigecycline and arginine when a solid composition including tigecycline and arginine is stored at 40 °C over a period of 6 months, at most 0.1 % of the tigecycline is converted to the 6-ene degradant, and at most 0.75% of the tigecycline is converted to the epimer degradant. More preferably, when a solid composition including tigecycline and arginine is stored at 40 °C over a period of 6 months, at most 0.09% of the tigecycline is converted to the 6-ene degradant, and at most 0.65% of the tigecycline is converted to the epimer degradant.
  • compositions containing tigecycline and arginine are stored at 40 °C over a period of 84 days, at most 2%, at most 1 .5% or at most 1% of the tigecycline degrades.
  • compositions containing tigecycline and arginine are stored at 55 °C over a period of 2 weeks, at most 2%, at most 1 .5% or at most 1% of the tigecycline degrades.
  • the solution when a solid composition including tigecycline and arginine is reconstituted with an aqueous carrier liquid to form a solution, the solution may be stable for more than 24 hours at 25 °C, and for at least 24 hours at elevated temperatures above 25 °C. In certain embodiments, when the solution is stored at 25 °C over a period of 24 hours, at most 2% of the tigecycline degrades. Preferably, when the solution is stored at 25 °C over a period of 24 hours, at most 1 .75%, 1 .5%, 1 .25% or 1 % of the tigecycline degrades. In certain embodiments, the solution has a tigecycline concentration of about 10 mg/mL, about 1 mg/mL, or about 0.5 mg/mL.
  • a solid composition including tigecycline and arginine is reconstituted with an aqueous carrier liquid to form a solution having a tigecycline concentration of about 1 mg/mL, and the solution is stored at 25 °C over a period of 24 hours, at most 0.5% of the tigecycline is converted to the 6-ene degradant, and at most 1 % of the tigecycline is converted to the epimer degradant. More preferably, at most 0.4% of the tigecycline is converted to the 6-ene degradant, and at most 0.8% of the tigecycline is converted to the epimer degradant.
  • At most 0.3% of the tigecycline is converted to the 6-ene degradant, and at most 0.7% of the tigecycline is converted to the epimer degradant. More preferably, at most 0.2% of the tigecycline is converted to the 6-ene degradant, and at most 0.6% of the tigecycline is converted to the epimer degradan ⁇ . More preferably, af most 0.1 % of the tigecycline is converted to the 6-ene degradant, and at most 0.5% of the tigecycline is converted to the epimer degradant.
  • compositions comprising tigecycline and arginine formed by lyophilizing solutions having a range of acidic pHs.
  • Solid compositions were formed by dissolving 87.5 mg arginine in water and adjusting the solution to an acidic pH. Tigecycline (53 mg) was added to this solution, providing a mass ratio of tigecycline to arginine of 1 :1 .05. The pH of individual solutions was adjusted to 4.5, 4.75, 5.1 , 5.25 or 5.5. The resulting solutions were clear, with no visible particles. The solutions were then filtered and lyophilized to form solid compositions. The lyophilization procedure was adjusted as need for each type of composition, as the collapse temperature of the composition was affected by the amount of arginine and by the pH.
  • the general procedure included reducing the temperature of the lyophilization solutions to -45 °C, performing a primary drying at a temperature of from -35 to -15 °C and under a vacuum of from 50-200 milliTorr (mTorr), and performing a secondary drying at a temperature of 25 °C or 40 °C.
  • the solutions for lyophilization were prepared at low temperature, using a nitrogen blanket and purging.
  • Each lyophilized composition was sealed in a 5 ml_ vial with a 13 mm rubber stopper, or in a 10 ml_ vial with a 20 mm rubber stopper and stored at 25 °C, 40 °C or 55 °C (all temperatures ⁇ 2 °C).
  • the stoppers were STELMI 6720GC (American Stelmi Corporation, Princeton, NJ). After 4, 8 and 12 weeks at 25 °C or 40 °C, and after 2 and 4 weeks at 55 °C, a portion of the vials were visually inspected with regard to the color of the solid, and were then reconstituted with 5.3 ml_ of 0.9% sodium chloride injection, USP.
  • Table 1 lists the results of these analyses for lyophilized compositions stored at 25 °C
  • Table 2 lists the results for lyophilized compositions stored at 40 °C
  • Table 3 lists the results for lyophilized compositions stored at 55 °C.
  • Table 1 Stability at 25 ⁇ 2 °C of tigecycline in solid compositions containing arginine. pH at Time pH at Moisture Impurities (%) lyophilization (weeks) reconstitution (%) 6-ene Epimer Total
  • Table 2 Stability at 40 ⁇ 2 °C of tigecycline in solid compositions containing arginine. pH at Time pH at Moisture Impurities (%) lyophilization (weeks) reconstitution (%) 6-ene Epimer Total
  • Table 3 Stability at 55 ⁇ 2 °C of tigecycline in solid compositions containing arginine. pH at Time pH at Moisture Impurities (%) lyophilization (weeks) reconstitution (%) 6-ene Epimer Total
  • the pH of the tigecycline solutions prior to lyophilization affected the stability of the tigecycline in the resulting solid compositions.
  • the concentration of the 6-ene oxidation product was lower in compositions formed from solutions having more acidic pH's of 4.5 and 4.75, and was higher in compositions formed from solutions having less acidic pH's of 5.25 and 5.5.
  • the concentration of the epimer was higher in compositions formed from solutions having more acidic pH's of 4.5 and 4.75, and was lower in compositions formed from solutions having less acidic pH's of 5.25 and 5.5.
  • the overall concentration of impurities was lowest in the solutions formed from lyophilization compositions having a pH of 5.1 or 5.25.
  • Other variables besides pH were examined. For example, some samples of the solid compositions were stored in upright vials, whereas other samples were stored in inverted vials in which the powder of the composition was in contact with the rubber stopper. No significant difference in
  • the solid compositions were stored in vials sealed with rubber stoppers that had been dried in an oven at 105 °C for 5 hours after sterilization, or were stored in vials sealed with rubber stoppers that were not dried after sterilization. Although the moisture content was slightly lower for solid compositions stored using dried stoppers, no significant difference in tigecycline stability was observed between the two types of stoppers.
  • compositions comprising tigecycline and arginine formed by lyophilizing solutions having a range of acidic pHs are storage stable at 25 °C, 40 °C, and 55 °C.
  • compositions formed from lyophilization compositions having a pH of 5.1 were stored in 10 ml_ vials sealed with a 20 mm stopper, rather than in 5 ml_ vials with a 13 mm stopper.
  • Compositions in the 10 ml_ vials also were analyzed for the effects of stopper drying and/or vial orientation on tigecycline stability. No significant difference in tigecycline stability was observed between the two orientations of vials or between the two types of stoppers.
  • Table 4 lists the results of the analyses for solid compositions stored in 5 mL or in 10 ml_ vials. The stability trends for compositions in the 10 mL vials were similar to the trends observed for compositions in the 5 mL vials.
  • Table 4 Stability of tigecycline in solid compositions containing arginine, in 5 ml_ vials and 10 ml_ vials.
  • Table 5 lists the results of stability analyses of lyophilized compositions containing tigecycline and one of a variety of excipients.
  • the results for the compositions containing arginine are reproduced from Table 2 above, for the lyophilized solids formed from a liquid having a pH of 5.1 .
  • the results for the conventional compositions containing lactose monohydrate are reproduced from U.S. Patent No. 7,879,828.
  • the results for the compositions containing ascorbic acid, threonine or serine are reproduced from Chinese patent publication CN 102138925 A.
  • Table 5 Stability at 40 °C of tigecycline in various solid compositions.
  • lyophilized compositions including tigecycline and arginine were more stable than comparable lyophilized compositions including
  • the composition containing arginine had an impurity concentration that was 74% less than the impurity concentration of the composition containing
  • lactose monohydrate after 25 days at 40 °C.
  • the arginine composition also had an impurity concentration after 56 days at 40 °C that was 76% less than that of the lactose monohydrate composition after only 48 days at 40 °C.
  • the lyophilized compositions containing ascorbic acid, threonine or serine were reported to be more stable than lyophilized compositions containing lactose monohydrate, the lyophilized compositions including tigecycline and arginine were even more stable.
  • the composition containing arginine had an impurity concentration that was 35%, 41% and 56% less than the impurity
  • the arginine composition had an impurity concentration that was 51 % and 50% less than the impurity concentrations of the ascorbic acid or threonine compositions, respectively, after 90 days at 40 °C.
  • tigecycline and ascorbic acid were stored at 40 °C over a period of 90 days, more than 2% of the tigecycline degraded, as determined by the total impurities of 2.02%.
  • the stability of a solid composition comprising tigecycline and arginine was compared to the stability of solid compositions comprising tigecycline and one of the following lyophilization excipients: glycine, asparagine, lysine, aspartic acid, dextran, mannitol, or methylcellulose.
  • glycine asparagine
  • lysine aspartic acid
  • dextran dextran
  • mannitol or methylcellulose.
  • Each composition was formed by dissolving the excipient in water and adjusting the solution to an acidic pH. Tigecycline was then added to each solution, and the solution pH was adjusted as needed to provide the pH listed in Table ⁇ .
  • the resulting solutions were clear, with no visible particles, and were filtered and lyophilized to form solid compositions, as described above with regard to Tables 1 -3, above.
  • Each lyophilized composition was sealed in a 5 ml_ vial with a 13 mm STELMI 6720GC rubber stopper, and stored at 55 ⁇ 2 °C (-75% relative humidity (RH)) .
  • RH relative humidity
  • a portion of the vials were visually inspected with regard to the color of the solid, and were then reconstituted with 5.3 ml_ of 0.9% sodium chloride injection, USP.
  • the reconstituted liquids were visually inspected, and were then analyzed by HPLC to determine the concentrations of tigecycline and of any impurities, including the 6-ene oxidation product and the epimerization product. Table 6 lists the results of these analyses, as well as the properties of the liquids used to form the lyophilized compositions.
  • Table 6 Stability, after 2 weeks at 55 ⁇ 2 °C, of tigecycline
  • Amount of tigecycline includes 6% overage.
  • the lyophilized composition including tigecycline and arginine was more stable fhan comparable lyophilized compositions including tigecycline and other amino acids. After 2 weeks at 55 °C, fhe composifion confaining arginine had a total impurity amount that was 89% less than that of the composifion containing glycine having a pH of 4.75 before
  • the lyophilized composifion including tigecycline and arginine was more stable than comparable lyophilized compositions including tigecycline and other lyophilization excipients.
  • the composition containing arginine had an impurity concentration that was 71 % less than that of the composition containing dextran, 85% less than that of the composition containing mannitol, and 84% less than that of the composition containing methylcellulose.
  • This example demonstrates the stability of solid compositions comprising tigecycline and arginine prepared under varying lyophilization conditions.
  • compositions having a range of arginine were determined in compositions having a range of arginine
  • Table 7 lists the results of stability analyses of lyophilized compositions containing tigecycline and arginine, where the arginine was present at one of a variety of concentrations from 50 mg/vial to 100 mg/vial, the pH was from 4.5 to 5.75, and the primary drying during lyophilization was -25 °C or -30 °C.
  • the compositions were formed and sealed in 5 mL vials as described with regard to Tables 1 -3, above.
  • Each lyophilized composition was stored for 2 weeks at 55 ⁇ 2 °C (-75% RH) and then analyzed for impurities as described with regard to Tables 1 -3, above. Table 7 lists the results of these analyses, as well as the concentrations of arginine in the lyophilized compositions.
  • Table 7 Stability, after 2 weeks at 55 ⁇ 2 °C, of tigecycline in solid compositions with various concentrations of arginine.
  • Amounts of tigecycline and arginine include 6% overage.
  • Tigecycline was stabilized in the lyophilized compositions, regardless of the concentration of arginine in the compositions, the pH of the lyophilization liquid, or the primary drying temperature, within the listed ranges.
  • the highest amount of impurity was 1 .58%, measured for a
  • the lowest amount of impurity was 0.82%, measured for a composition having 100 mg/vial arginine and formed from a lyophilization liquid having a pH of 5.75 using a primary drying temperature of -30 °C.
  • the combination of tigecycline with arginine appeared to stabilize the tigecycline in a variety of different solid compositions.
  • solid compositions having a mass ratio of tigecycline to arginine of from 1 :1 ⁇ o 1 :2, and formed from liquids having a pH before lyophilization of from 4.5 to 5.75, allowed for less than 1 . ⁇ % impurities in the composition when stored for 2 weeks at 55 ⁇ 2 °C.
  • compositions comprising tigecycline and arginine exhibit greater stability when compared with the TYGACILTM formulation.
  • Table 8 provides a summary of the amount of tigecycline epimer, 6-ene oxidation product, and total impurities (imp) formed in three lots of a composition according to the invention as compared to a lot of the
  • TYGACILTM formulation following storage at 40 °C.
  • Each vial of each lot of the composition of the invention contained 53 mg tigecycline and 87.5 mg arginine, and demonstrated a reconstituted pH in the range of 4.25-5.75.
  • Each vial of the TYGACILTM formulation contained 53 mg tigecycline and 10 ⁇ mg lactose monohydrate, and demonstrated a reconstituted pH of approximately 5.
  • TYGACILTM 6-ene ⁇ 0.05 0.06 ⁇ 0.05 ⁇ 0.05 NT total imp 0.79 1 .26 1 .31 1 .50 NT
  • compositions comprising tigecycline and arginine
  • Table 9 provides a summary of the amount of tigecycline epimer, 6-ene oxidation product, and total impurities (imp) formed in three lots of a composition according to the invention following storage af 25 °C.
  • Each vial of each lot of the composition of the invention contained 53 mg tigecycline and 87.5 mg arginine, and demonstrated a reconstituted pH in the range of 4.25-5.75. Stability at 25 ⁇ 2 °C / 60 ⁇ 5% RH of tigecycline in solid compositions containing arginine
  • Each solid was reconstituted in a 5.3 mL volume of 0.9% sodium chloride reconstitution liquid, to provide reconstituted solutions having tigecycline concentrations of 10 mg/mL. Aliquots of 5 mL of each reconstituted solution, which contained 50 mg tigecycline, were then diluted with 50 mL of an infusion liquid to provide diluted solutions having final concentrations of
  • Table 10 Stability of tigecycline in reconstituted and diluted liquids.
  • Tigecycline was more stable in reconstituted and diluted liquids formed from solid compositions containing arginine than in those formed from conventional solid compositions containing lactose monohydrate.
  • the diluted liquid formed from a solid composition containing arginine had an initial impurity level of 0.92% at 25°C
  • the diluted liquid formed from a solid composition containing lactose monohydrate had a higher initial impurity level of 1 .47% at 25°C.
  • the impurity levels of the liquids were 1 .42% and 1 .90%, respectively. Similar room temperature stability trends were observed when the infusion liquid was 5% dextrose injection or lactated Ringer's injection.

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Abstract

L'invention concerne une composition de tigécycline comprenant de la tigécycline et de l'arginine, la composition étant un solide. La composition solide peut être réalisée par formation d'un mélange liquide contenant un solvant, de la tigécycline et de l'arginine, puis lyophilisation du mélange liquide.
EP14792101.9A 2013-04-30 2014-04-30 Formualtions de tigécycline Withdrawn EP2991632A4 (fr)

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